AG-957 is a tyrphostin which inhibits the in vitro growth of the human CML cell line K562 at concentrations of approximately 10 to 20 microM. AG-957 also blocks in vitro phosphorylation of p210bcr-abl in these cells. Development of AG-957 as a chemotherapeutic candidate, however, is impeded by the low potency of the compound, and rapid in vivo metabolism, making it impossible to achieve effective plasma concentrations. The objective of this project is to define the pharmacological properties of AG-957 and a number of its analogs in order to provide a basis for the design of a molecule whose plasma concentrations can be maintained at or above its effective levels. AG- 957, was eliminated very rapidly following IV injection in mice. The biological half-life was approximately 4 minutes. An increase in the plasma levels of a metabolite identified as the carboxyllic acid of AG- 957 corresponded with the decrease in the concentrations of the parent compound. This suggested that esterase catalyzed cleavage of the methyl ester group of AG-957 is a primary route of metabloic degredation of the compound. For this reason, the initial studies have focused on the influence on biological half-life of modifications of the methyl ester moiety of AG-957. To date, pharmacokinetic studies have been conducted with four analogs of AG-957, the isopropyl ester, t-butyl ester, phenyl- methyl ester, and an analog with the ester group replaced with an amide. The biological half-life of the isopropyl ester was 17 minutes, which was an improvement over the parent compound, but still rapid. The phenyl- methyl ester and the t-butyl each showed an additional improvement, with a half-lives of 56 and 101 minutes respectively. The amid had the longest biological half-life, which was 188 minutes. These results indicate that metabolism can be decreased by increasing the degree of substitution of the ester group or by eliminating the ester group completely. While some of the compounds tested showed significantly improved biological half-lives over AG-957, elimination was still rapid enough that maintaining continuous plasma concentrations in the effective range (10-20 microM) would be difficult to achieve. Additional analogs with modifications to the ester moiety, as well as other parts of the molecule, will be tested in an attempt to characterize structural elements which will minimize elimination.